HIF-2α promotes hypoxic cell proliferation by enhancing c-Myc transcriptional activity

HIF-2 alpha promotes von Hippel-Lindau (VHL)-deficient renal clear cell carcinoma (RCC) tumorigenesis, while HIF-1 alpha inhibits RCC growth. As HIF-1 alpha antagonizes c-Myc function, we hypothesized that HIF-2 alpha might enhance c-Myc activity. We demonstrate here that HIF-2 alpha promotes cell-cycle progression in hypoxic RCCs and multiple other cell lines. This correlates with enhanced c-Myc promoter binding, transcriptional effects on both activated and repressed target genes, and interactions with Sp1, Miz1, and Max. Finally, HIF-2 alpha augments c-Myc transformation of primary mouse embryo fibroblasts (MEFs). Enhanced c-Myc activity likely contributes; to HIF-2 alpha-mediated neoplastic progression following loss of the VHL tumor suppressor and influences the behavior of hypoxic tumor cells.